Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.

Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD. Synopsis: Metabolic Reprogramming, such as glycolysis and glutaminolysis, are key features of polycystic kidney disease (PKD). Asparagine synthetase drives glutamine utilization in this disease and it is upregulated in human and mouse tissues. Its inhibition retards disease progression and rescues metabolic derangement in PKD mice. Glutamine utilization and cyst expansion are driven by ASNS upregulation in PKD. PKD cystic phenotype and metabolic rewiring are hampered by Asns-ASO. Glutaminolysis, pyrimidine biosynthesis and proliferation are driven by a GCN2-ATF4-ASNS axis. PKD is further delayed by co-targeting glutaminolysis and glycolysis with Asns-ASO and 2DG. Metabolic Reprogramming, such as glycolysis and glutaminolysis, are key features of polycystic kidney disease (PKD). Asparagine synthetase drives glutamine utilization in this disease and it is upregulated in human and mouse tissues. Its inhibition retards disease progression and rescues metabolic derangement in PKD mice. [ABSTRACT FROM AUTHOR]